SPID#: 13 SIVHU was isolated from an individual who seroconverted to HIV-2/SIV while working with SIV. The individual remains asymptomatic six years after seroconversion, with evidence of extremely low proviral loads, and low, yet stable antibody titers. Sequence analysis of LTR, vpr, env and nef regions of SIVHU show it closest (96-98% homology) to SIVB670, a sooty mangabey strain with which the individual has primarily worked. Sequences of LTR, vpr, and env revealed no abnormalities of obvious functional significance. In contrast, the nef sequence showed a 4 base deletion, a downstream premature stop codon, and a predicted truncation at amino acid 175. Nef sequence of SIVB670 predicted a full-length protein. Experimental infection of three macaques with SIVHU and three other macaques with SIVB670, resulted in seroconversion in all six animals. All three SIVB670 animals died of AIDS-related illnesses at 8.5 and 18 months post inoculation. In contrast, all three SIVHU-infected monkeys remain healthy at 24 months post inoculation, show evidence of lower viral loads and antibody titers when compared with the SIVB670- animals, and maintain nef truncation. These results provide additional evidence for the role of intact nef in the pathogenicity of SIV in macaques, and extend our knowledge on the role of nef in SIV attenuation in humans.